We have discovered molecular profiles of inflammatory cytokines that identify lung cancer, its different histological types and prognosis. We measured the expression levels of these genes in noncancerous lung tissue and paired primary lung tumor tissue of 80 patients (stage I-IV) from the NCI-Maryland Lung Cancer Case-Control Study and 50 patients (stage I) from Tokyo or Hamamatsu, Japan. Expression patterns of these genes in noncancerous tissue were capable of predicting tumor metastasis. Expression patterns from tumor tissue were significantly associated with poor prognosis. Using this information, we developed the Cytokine Lung Adenocarcinoma Survival Signature (CLASS-11) which predicts disease prognosis independent of staging. More importantly, this signature can predict prognosis in stage I patients to identify individuals at high risk of disease progression before metastasis is evident. This association was first found in the American cohort and was then validated in the Japanese cohort. This study demonstrates the potential of CLASS-11 signature as a clinical biomarker to predict prognosis of lung cancer and may be especially useful in stage I cases.